藉由藥效基團模型、虛擬篩選、分子嵌合及分子動態模擬來搜尋新型的抗動脈粥狀硬化症化合物

Discovery of novel anti-atherosclerotic compounds by pharmacophore modeling, virtual screening, molecular docking and molecular dynamics simulations.

陳沐家(Mu-Jia Chen)

指導教授 ： 劉宣良

國立臺北科技大學/工程學院/生物科技研究所/碩士(2012年)

摘要

動脈粥狀硬化症是由於長時間的脂質與膽固醇堆積於動脈血管壁中，其產生的硬塊使血管變得狹窄，而導致心血管疾病的發生。過去的文獻指出，已有大量的抗動脈粥狀硬化症藥物被開發，然而，其藥物卻有多種的副作用出現在人類及動物的活體實驗中。至今，尚缺乏一個有效且不具副作用的抗動脈粥狀硬化症藥物，為了尋找更有效更低副作用的藥物，我們採用多種電腦輔助藥物設計原件包含了藥效基團、虛擬篩選、分子嵌合與分子動態模擬來進行本次實驗。在先前的研究指出，醯基-輔酶A:膽固醇醯基轉移酶與膽固醇酯轉移蛋白對於動脈粥狀硬化症皆扮演重要角色。醯基-輔酶A:膽固醇醯基轉移酶存在兩種相似的型態，故我們分別針對第一型與第二型醯基-輔酶A:膽固醇醯基轉移酶架設以配體為基礎的HipHopRefine與HypoRefine的藥效基團模型，並在經過Güner–Henry (GH) 評分方法驗證後都顯示兩者皆具有好的預測能力，接著我們結合這兩種模型並以虛擬篩選模組進行ZINC化學資料庫之篩選，而最後十個化合物對於這兩者藥效基團具有高吻合度並有多樣化骨幹結構將作為未來藥物開發上可能的前導藥物。另一方面，我們以一系列膽固醇酯轉移蛋白的抑制劑來架構HipHop藥效基團模型，而其中最好的模型(HipHop-1)具有最高的GH評分分數，故我們以此模型套用到NCI及Maybridge化學資料庫的虛擬藥物篩選，再經由分子嵌合及分子動力模擬的方法來篩選出四個最具好結合力的化合物。而本實驗所挑選出來的化合物可應用於日後設計新型並更具活性的抗動脈粥狀硬化症用藥來達到臨床上的應用。

關鍵字

動脈粥狀硬化症 ； 醯基-輔酶A:膽固醇醯基轉移酶膽固醇酯轉移蛋白 ； 藥效基團 ； 虛擬篩選 ； 分子嵌合 ； 分子動態模擬

並列摘要

Atherosclerosis is a chronic inflammatory disease characterized by the accumulation of lipids and fibrous elements in the large arteries; moreover, it is the primary cause of cardiovascular diseases. In previous studies, a great number of anti-atherosclerotic drugs have been developed but several side effects were found in animal and human studies. Until recently, an effective anti-atherosclerotic drug without side effects has not been discovered. Therefore, we applied many computational approaches including pharmacophore modeling, virtual screening, molecular docking and molecular dynamic for searching more effective and less side effects anti-atherosclerotic drugs. Furthermore, it was found that there are two predominant targets for anti-atherosclerotic: Acyl-coenzyme A: cholesterol acyltransferase (ACAT) and Cholesteryl ester transfer protein (CETP). For ACAT, there are two similar types ACAT-1 and ACAT-2, and then we constructed ligand-base pharmacophore models: HipHopRefine and HypoRefine for ACAT-1 and ACAT-2 respectively. After Güner–Henry (GH) scoring methods validation, both of HipHopRefine and HypoRefine show good predictive ability. Subsequently, we utilized two pharmacophore models to screen ZINC database for obtaining more potential dual ACAT inhibitors. After virtual screening, 10 hits with high pharmacophore fitvalue and diverse scaffolds were identified as potential lead compounds. As to CETP, we also constructed HipHop pharmacophore model by a series of CETP inhibitors to search another potential drugs of atherosclerosis. The best model HipHop-1 was further validated by GH scoring methods and applied to screen the NCI and Maybridge databases. Then, molecular docking and molecular dynamic were conducted to retrieve 4 potential compounds. In summary, the results of this study can be applied to the design of new and more potent anti-atherosclerotic drugs for clinical purposes.

並列關鍵字

Atherosclerosis ； Acyl-coenzyme A: cholesterol acyltransferase (ACAT) ； Cholesteryl ester transfer protein (CETP) ； pharmacophore ； virtual screening ； molecular docking ； molecular dynamic

參考文獻

Agellon LB, Quinet EM, Gillette TG, Drayna DT, Brown ML, Tall AR (1990) Organization of the human cholesteryl ester transfer protein gene. Biochemistry 29(6):1372–1376

Aragane K, Kojima K, Fujinami K, Kamei J and Kusunoki J (2001) Effect of F-1394, an acyl-CoA:cholesterol acyltransferase inhibitor, on atherosclerosis induced by high cholesterol diet in rabbits. Atherosclerosis 158, 139-145.

Asami Y, Yamagishi I, Murakami S, Araki H., Tsuchida K and Higuchi S (1998) HL-004, the ACAT inhibitor, prevents the progression of atherosclerosis in cholesterol- fed rabbits. Life. Sci. 62, 1055-1063.

Berti JA, de Faria EC and Oliveira HC (2005) Atherosclerosis in aged mice over-expressing the reverse cholesterol transport genes. Braz. J. Med. Biol. Res. 38, 391–398.

Bocan TM, Mueller SB, Uhlendorf PD, Newton RS and Krause BR (1991) Comparison of CI-976, an ACAT inhibitor, and selected lipid-lowering agents for antiatherosclerotic activity in iliac-femoral and thoracic aortic lesions. A biochemical, morphological, and morphometric evaluation. Arterioscler. Thromb. 11, 1830-1843.